Project Summary There is consistent evidence for the influence of person-environment interplay in the development of adolescent SU and SUDs, such that adverse environmental contexts appear to amplify dispositional risk and protective environmental contexts appear to offset dispositional risk for SU. Although this has been demonstrated across key adolescent family, peer, and school factors in relation to adolescent SU, there is a dearth of research evaluating person-environment interplay in relation to adult onset SUDs or overall SUD course (i.e., recurrence, desistence) into adulthood. Given that the majority of SUDs are adult onset and that recurrent SUD is associated with particularly problematic health consequences (e.g., early death), it is crucial to fill this gap. We hypothesize that similar mechanisms of person-environment interplay that have been demonstrated for adolescent SU continue to operate in adulthood, but that the environmental factors that offset or amplify risk for adult onset and recurrent SUD course will be those that are most relevant to adult development. Thus, much like aspects of the adolescent parent-child, peer, and school context are expected to moderate dispositional risk for adolescent onset SUD (H1), aspects of adult romantic partner, family, peer, education, and employment context are expected to moderate dispositional risk for adult onset SUD and overall course (H2). We expect distal environmental contexts (those that happened long ago, i.e., adolescence) will only be relevant to adult onset SUD and recurrence insofar as they are mediated through more proximal adult environmental contexts (e.g., adult peer and romantic partner characteristics) (H3). To investigate these hypotheses, we propose a series secondary analyses of the population-based Minnesota Twin and Family Study (MTFS; R37DA005147, R01AA009367). The MTFS (N = 2,769, 52% female) has six prospective waves of rich data collected from preadolescence (age 11) through young adulthood (age 29). In this study, dispositional risk will be measured using personality scales shown to be highly relevant to SUDs (aggressive undercontrol, negative emotionality, and constraint). This study focuses on alcohol use disorder given it is the most prevalent SUD, but will directly compare similarity of etiologies with illicit drug use disorder (e.g., cannabis). This study is innovative because it will evaluate person-environment interplay in relation to trajectories of clinically diagnosed SUDs rather than focusing on adolescent SU alone. Investigation of the proposed hypotheses will elucidate key factors important to disrupting or amplifying the cascading development of recurrent SU problems, which provides invaluable information regarding the most critical and cost-effective points of entry for SUD prevention and intervention. The proposed study is significant as it will address a key gap in the research and will advance knowledge on the etiology of SUD onset and trajectory. Findings will clarify which environmental contexts are most relevant to amplifying or offsetting risk for developmentally-limited versus recurrent SUD course, which is crucial to guiding prevention not only in adolescence, but also in early and later young adulthood when SUDs are most prevalent.